PARL stabilizes mitochondrial BCL-2 via Nur77-mediated scaffolding as a therapeutic strategy for Parkinson’s disease

Parkinson’s disease (PD) involves both mitochondrial dysfunction and Lewy body pathology. However molecular links between these features remain unclear. Here, we identify Presenilin-associated rhomboid-like protein (PARL) as a Lewy body component, RARL regulates mitochondrial apoptosis via interacting with orphan nuclear receptor Nur77. Clinical profiling revealed reduced plasma PARL levels in 71 PD patients versus controls (p < 0.001), which correlated with disease severity. In MPP+/MPTP models, PARL depletion amplified BAX activation and caspase-3 cleavage, driving neuronal death. Mechanistically, mitochondrial translocation of Nur77 stabilized PARL-BCL-2 complexes, suppressing apoptosis. AlphaFold2-guided structural modeling uncovered a PARL α-helix essential for Nur77 binding. Disrupting this interface abolished BCL-2 stabilization. Parl knockdown exacerbated motor/cognitive deficits in MPTP mice, rescued by Nur77 overexpression. Subcellular tracking demonstrated Nur77 nuclear-cytoplasmic shuttling dynamically regulates PARL-BCL-2 assembly, while co-immunoprecipitation confirmed Nur77 knockdown dissociates this complex. Our findings define the Nur77-PARL axis as a critical mitochondrial gatekeeper in PD, where PARL serves dual roles as a Lewy body constituent and apoptosis regulator. Reduced circulating PARL levels may reflect disease progression, while the Nur77-PARL structural interface offers a therapeutic target for neuroprotection. This study bridges Lewy body biology with mitochondrial apoptosis. It proposes biomarker-driven strategies to modulate BCL-2-dependent neuronal survival in PD.